As described in copending U.S. patent application Ser. No. 11/331,324, filed Jan. 12, 2006 (herein, “the '324 application”), the disclosure of which is incorporated herein in its entirety by reference, himbacine analogs are useful as thrombin receptor antagonists. Thrombin is known to have a variety of activities in different cell types. Thrombin receptors are known to be present in such diverse cell types as human platelets, vascular smooth muscle cells, endothelial cells, and fibroblasts. Thrombin receptor antagonists may be useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role, for example, as described in U.S. Pat. No. 6,063,847, the disclosure of which is incorporated by reference. Additional examples of thrombin receptor antagonists useful in the treatment of thrombotic, inflammatory, atherosclerotic, and fibroproliferative disorders, and the synthesis of these compounds, are described in published U.S. Patent Application No. 2003/0216437 (herein, “the '437 publication”), the disclosure of which is incorporated herein in its entirety by reference.
One thrombin receptor antagonist identified is an orally bioavailable compound derived from himbacine having the structure of the compound 11:
Processes for the synthesis of this and similar himbacine analog thrombin receptor antagonists are disclosed in U.S. Pat. No. 6,063,847, and U.S. publication no. 2003/0216437, methods of using thrombin receptor antagonists are disclosed in U.S. publication no. 2004/0192753, and the synthesis of the bisulfate salt of a particular himbacine analog is disclosed in U.S. publication no. 2004/0176418, the disclosures of which are incorporated by reference herein.
As described in the '324 application mentioned herein above, compound 11 may be synthesized from Compound 15:
by treatment with compound 16 in accordance with Scheme I.

Compound 15 is in turn prepared from compound 1:
wherein R5 and R6 are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups, in four steps in accordance with the synthesis scheme shown in the copending '324 application, which synthetic schemes are incorporated herein by reference.
The copending '324 application describes the preparation of compound 16 in accordance with Scheme II, below.
With reference to Scheme II, L is a leaving group selected from halogens, esters, sulfonates and phosphates, R9 is selected from alkyl, aryl heteroaryl and arylalkyl groups having 1 to 10 carbon atoms, and R11 is selected from alkyl, aryl heteroaryl and arylalkyl groups having 1 to 10 carbon atoms and hydrogen. As described in the '324 application, in the scheme for preparation of compound 16, compound 36 is converted to compound 37 by first treatment with sodium carbonate to liberate the pyridyl alcohol free base, and the alcohol is subsequently reacted to convert the hydroxyl group to a leaving group (L) which can be displaced by a phosphite reagent to form the corresponding phosphonate ester. Accordingly, as described in the '324 application, preferably compound 37 is prepared by heating a solution of the alcohol intermediate isolated from compound 36 with a reagent that converts the hydroxyl functional group to a leaving group which can be displaced by a diorgano-phosphite compound. Preferably, L is a halogen, preferably Cl, and is preferably prepared by treating the alcohol with a halogenation reagent, for example, PBr3, PCl3, PCl5, and thionyl chloride, preferably thionyl chloride, followed by quenching the reaction with sodium carbonate, and extracting the product into toluene.
Compound 37 contained in the toluene extract is converted to compound 38 by reacting a solution of compound 37 with a diorgano-phosphite in the presence of a strong base, for example, a metal alkyl, for example, lithium alkyl and a metal amide, for example lithium bis(trimethylsilyl) amide.
The conversion of compound 38 to compound 16 is done by reacting compound 38 with boronate, the reaction catalyzed by a palladium catalyst. The catalyst used can be a homogeneous catalyst, for example, a palladium phosphine, for example, palladium tristriphenyl phosphine, and palladium tris-ortho-tolyphosphine, and amine catalysts, for example, bispalladium-trisbipyridine, or a heterogeneous catalyst, for example, palladium supported on carbon black.
The scheme presented in the '345 application for the synthesis of compound 16, a critical intermediate in the preparation of a variety of thrombin receptor antagonists, requires isolation or extraction of intermediates in two of the four steps, and utilizes in one step a powerful base and a water sensitive diorgano-phosphite compound. Moreover, the step shown in Scheme II of reacting unisolated compound 38 with boronate to form compound 16 proved to provide variable results, rendering the process of Scheme II undesirable for use in the preparation of commercial quantities of material.